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Triple-negative breast cancer (TNBC) is characterized by unique aggressive behavior and lack of targeted therapies. Among the various molecular subtypes of breast cancer, it was observed that TNBCs express elevated levels of sphingosine kinase 1 (SPHK1) compared to other breast tumor subtypes. High levels of SPHK1 gene expression correlated with poor overall and progression- free survival, as well as poor response to Doxorubicin-based treatment. Inhibition of SPHK1 was found to attenuate ERK1/2 and AKT signaling and reduce growth of TNBC cells in vitro and in a xenograft SCID mouse model. Moreover, SPHK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBCs to chemotherapeutic drugs. Our findings suggest that SPHK1 inhibition, which effectively counteracts oncogenic signaling through ERK1/2 and AKT pathways, is a potentially important anti-tumor strategy in TNBC. A combination of SPHK1 inhibitors with chemotherapeutic agents may be effective against this aggressive subtype of breast cancer.

BACKGROUND AND PURPOSEActivation of signal transducer and activator of transcription 3 (STAT3) play a critical role in the survival, proliferation, angiogenesis and chemoresistance of tumour cells. Thus, agents that suppress STAT3 phosphorylation have potential as cancer therapies. In the present study, we investigated whether the apoptotic, antiproliferative and chemosensitizing effects of g-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC). EXPERIMENTAL APPROACHThe effect of g-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated. KEY RESULTSg-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. g-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the g-tocotrienolinduced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that g-tocotrienol induced the expression of the tyrosine phosphatase SHP-1 and deletion of the SHP-1 gene by small interfering RNA abolished the ability of g-tocotrienol to inhibit STAT3 activation. g-Tocotrienol also down-regulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, g-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC. CONCLUSIONS AND IMPLICATIONSOverall, these results suggest that g-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers. BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) IntroductionHepatocellular carcinoma (HCC) is the fifth most common cancer in the world, with an estimated incidence of half a million new cases per year around the world (El-Serag and Rudolph, 2007;Berasain et al., 2009). The HCC is characterized as a highly chemoresistant cancer with several aetiological factors being classified as high-risk factors, including exposure to aflatoxin B1, and infection with hepatitis B virus and hepatitis C virus (Kern et al., 2002;Farazi and DePinho, 2006). First line chemotherapeutic drugs currently being used for HCC therapy include doxorubicin, fluorouracil, cisplatin, and mitomycin, but most of these exhibit significant side effects (Avila et al., 2006;Kerr and Kerr, 2009;Rampone et al., 2009). Therefore, the need to develop more therapeutic strategies for HCC that are non-toxic and efficacious is of paramount importance. Anticancer drug discovery from agents derived from natural sources provides a great opportunity to improve the existing standard of care for HCC and other cancers (Newman, 2008). One such agent is, g-tocotrieno...